The present invention relates generally to antimicrobial agents and, in particular, to stabilized, metal-based antimicrobial agents suitable for topical applications in the prevention and treatment of infections and as a treatment for medical devices to make them infection resistant.
Antimicrobial agents are chemical compositions that inhibit microbial growth or kill bacteria, fungi and other microorganisms. The antimicrobial activity of inorganic substances is generally related to the ions into which they dissociate. The antimicrobial activity of various metal ions, for example, is often attributed to their affinity for protein material and the insolubility of the metal proteinate formed. Metal-containing salts are thus among the inorganic substances that act as antimicrobial agents.
Infection is a common complication associated with the use of medical devices. Various techniques have been described that incorporate potentially toxic metal ions in the form of metal salts into the materials which make up these medical devices. For example, U.S. Pat. No. 4,603,152, describes an antimicrobial composition useful in providing antimicrobial coatings on medical devices. In this composition, particles of antimicrobial metal compounds are mixed in a polymer matrix and coated onto a medical device to provide antimicrobial protection on that device. U.S. Pat. No. 4,054,139 describes a catheter wherein the exterior and interior surfaces of the catheter have fixed and exposed thereon an effective quantity of silver-bearing, immobile, oligodynamic material which provides the catheter with antimicrobial protection.
The major shortcoming of these methods relates to the poor solubility and consequent slow surface diffusion of the metal salt in the hydrophic and lipophilic material matrix that makes up the medical devices.
Indeed, because the antimicrobial metal salt must be on the surface of the medical device, the antimicrobial protection of the medical implant will last only as long as the metal-salt or compound is on the surface. Additionally, certain metal ions, especially silver ions, are not photostable and, upon exposure to light are reduced to a metal, thereby losing antimicrobial efficacy.
If, on the other hand, metal-salt compounds are added to a separate polymer composition which is then used to coat the surface of the medical device, a problem arises because the coating of an implant with a separate polymer composition may change the dimensions of the medical device. Although this may not be important to medical devices such as wound dressings, a change in size of a medical implant such as a catheter may affect its usefulness.
In U.S. Pat. No. 4,581,028, Fox describes a method for making infection-resistant materials by treating an implant first with an aqueous solution of a sulfonamide salt then with an aqueous solution of a silver salt such as silver nitrate. Fox believed that the silver ion would chelate to the sulfonamide anion on the surface of the polymer and this would provide longer lasting antimicrobial efficacy than would simple treatment of the implant with silver nitrate solution because the silver-sulfonamide salt would solvate into the surrounding environment more slowly.
Romans, U.S. Pat. No. 3,092,552, discloses the use of silver ion as an oligodynamic agent in a therapeutic or surface-treating composition or as an effective means for germicidally protecting an article or surface. Specifically, the disclosed composition is comprised of a low concentration of a silver compound such as silver nitrate or silver oxide, a reducing agent such as starch or sugar, polyethylene glycol (PEG) and urea. This patent further teaches the addition of small amounts of sodium chloride or cupric chloride to the composition to prevent discoloration even when the product is exposed to sterilization procedures and direct sunlight. The presence of metal ions such as copper and/or zinc is thought to stabilize the silver ion, making it more selective in its germicidal activity. Although Romans teaches that the quantities of these metals in the composition should vary, he states that the ratio of copper and/or zinc to silver should be no greater than 2:1.
Another reference teaching pharmaceutical compositions comprised of polyethylene glycol, a metal cation and an anion, is Kaplan, U.S. Pat. No. 4,451,447. Specifically, this reference teaches a composition comprised of cisplatin, PEG and a source of chloride ion, such as sodium chloride, to be used in treating human neoplasms. Kaplan teaches that complexation of the cisplatin with PEG prevents crystallization of the cisplatin during storage and thereby maintains pharmaceutical activity. The compositions do not appear to be photostable in that Kaplan explicitly teaches against exposing the composition to light.